Kirsten rat sarcoma viral oncogene homolog (G12S mutant) (KRAS (G12S))

KRAS (Kirsten rat sarcoma viral oncogene homolog) is a small GTPase enzyme that plays a central role in regulating cell growth, division, and survival through signal transduction pathways such as MAPK/ERK and PI3K/Akt/mTOR. The "G12S" designation refers to a specific somatic point mutation where glycine at position 12 is replaced by serine. This alteration results in constitutive activation of the KRAS protein, leading to uncontrolled cell proliferation and contributing directly to cancer development—especially pancreatic ductal adenocarcinoma but also other solid tumors. While direct pharmacological inhibition of most KRAS mutants has historically been challenging due to structural features that limit drug binding, recent advances have enabled selective targeting of certain mutations like G12C with approved drugs. For the less common but clinically significant G12S variant, novel covalent inhibitors have been developed that specifically acylate the acquired serine residue at position 12; these agents show promise for selectively suppressing oncogenic signaling in cancer cells harboring this mutation without affecting wild-type or other forms of KRAS. Detection of this mutation serves as both a diagnostic biomarker and a criterion for targeted therapy trials.

Other names

KRAS G12SK-Ras(G12S)KRAS glycine 12 serine mutantK-Ras G12S mutant

Covalent inhibition of the acquired serine at position 12 in the KRAS protein, suppressing oncogenic signaling specific to cells expressing the G12S mutation while sparing wild-type protein